prolongation of life span of disease model mice by low...
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Prolongation of Life Span of Disease Model Mice by Low Dose Rate Irradiation
Kazuo Sakai
Low Dose Radiation Research CenterCentral Research Institute of Electric Power Industry
(Presently: National Institute of Radiological Sciences)
Effects of Low Dose Rate Irradiation on Mice
• Suppression of Tumorigenesis– Radiation-Induced Thymic Lymphoma– Chemically-Induced Skin Tumor
• Suppression of Disease Development– Diabetes, Type I and Type II– Fatty Liver by CCl4
• Life Span Prolongation
1. Type II Diabetes
Female BKS.Cg-+Leprdb/+Leprdb/Jcl (C57BL/KsJ-db/db)
Dose Rate: 0.70mGy/ hr(10 Weeks Old at the Beginning of the Irradiation)
0 100 150500
20
40
60
80
100
Prolongation of Life Span of db/db Miceby Low Dose Rate Irradiation
0.70mGy/hr
Non IrradiatedSur
viva
l (%
)
Age (Weeks)
Effects of Low Dose Rate Irradiation on Life Span of db Mice
15012090603000
20
40
60
80
100
Non-Irradiated0.35 mGy/hr Irradiated0.70 mGy/hr Irradiated1.2 mGy/hr Irradiated
Su
rviv
ial R
atio
(%
)
1501209060300Week of Age
89.3 ± 4.8 103.3 ± 4.2*Life Span (Weeks)
142
134
Irradiated from 10 weeks
- -
Sur
viva
l (%
)
Appearance of db/db Mice at 90 Weeks of Age
Non-Irradiated
Irradiated
Abnormal Glucose Metabolism etc.
Decreased Insulin Level Increased Glucose Level
Glucose Radicals
Tissue Damage through Glycation
Complications
Shorter Life Span
Impaired B Cell Function
Possible Mechanism for Life Span Prolongation in Diabetic Mice
Abnormal Glucose Metabolism etc.
Decreased Insulin Level Increased Glucose Level
Glucose Radicals
Tissue Damage through Glycation
Complications
Shorter Life Span
Impaired B Cell Function
Possible Mechanism for Life Span Prolongation in Diabetic Mice
IncreasedAntioxidants
Female MRL-lpr/lpr Mice
Lack in Apoptosis, Which Removes Self-Attacking Lymphocytes.
Y
2. Severe Autoimmune Diseases
Dose Rate: 0.35 or 1.2mGy/ hrDuration: 7wk to 12wk of Age
orLife Span Long
abcde
0.35 mGy/hr
1.2 mGy/hr
Prolongation of life span in MRL-lpr/lpr mice with chronic low dose rate irradiation
Effects of Low Dose Rate Irradiation on Immunological Parameters
0
0.5
1
1.5
2
2.5R
elat
ive
Imm
unol
ogic
al P
aram
eter
s
0 0.35 1.2
Dose Rate (mGy/hr)
CD8+ cells in spleen
(Measured after 7 wk irradiation)
0
0.2
0.4
0.6
0.8
1
1.2
Rel
ativ
e Im
mun
olog
ical
Par
amet
ers
0 0.35 1.2
Dose Rate (mGy/hr)
(Measured after 7 wk irradiation)
Effects of Low Dose Rate Irradiation on Immunological Parameters
CD3+B220+
B220+CD40+
3. Klotho: A Premature Aging Model Mouse
Established in An Attempt to make disease model mice by shot-gun strategy.
Short life.Show symptoms similar to premature aging syndromes.Responsible gene is involved in calcium metabolism.
For Examination of Low Dose Rate Effect,Female 4 wks oldDose Rates 0.35, 0.70 or 1.2 mGy/hr 137Cs Gamma-RaysLife Long Irradiation from 4th week of age
Effects of Low Dose Rate Irradiation on Life Span of klotho mice
Start at28 days
8060402000
20
40
60
80
100
Time after Irradiation
Su
rviv
al R
atio
(%
)
Non-Irradiated0.35 mGy/hr Irradiated0.70 mGy/hr Irradiated1.2 mGy/hr Irradiated
(weeks)6420
(days)
12010080604020
Age (days)
8 10 12
Sur
viva
l (%
)
Effects of very low dose rate gamma irradiationon life span in C57BL/6 mice (1)
Caratero et al., Gerontology 44, 272-276 (1998)
Irradiated with gamma rays from thorium nitrate placed under the floor of cages.
Research Institute of Environmental Sciences(Rokkasho, Aomori)
continuous exposure to low dose rate radiation0 mGy/day0.05 mGy/day1.1 mGy/day21 mGy/day
Starts at50 days old
Stops at 450 days old
natural death& autopsy, pathology
Survival curves of B6C3F1 mice
Age (days) Age (days)
Sur
viva
l (%
)
A : Male B : Female
Tanaka, S. et.al. Rad. Res. 160: 376 - 79. (2003)
Effects of very low dose rate gamma irradiationon life span in C57BL/6 mice (2)
Courtade et al. Int. J. Radiat. Biol. 78, 845-855 (2002)
(10 mGy/yr)
Summary of Effects of Very Low Dose Rate Irradiation on C57BL/6 Mice
Same as above2710
SPFLess Crowded
270
Same as above2414
Same as above247
Conventional More Crowded
200
Conditions for Animal Care
50 % Survival Time (months)
Dose Rate(cGy/yr)
Summary of Effects of Low Dose Rate Irradiation on Life Span in Mice
NoSPFB6C3F1NoSPFC57BL/6
YesConventionalC57BL/6YesSPFklothoYesSPFlprYesSPFdb
Life Span Prolongation
Conditions for Animal Care
Strain
Low Dose Rate Irradiation and Life Span
Maximum Life Span
Shortened Life Span
Untoward Conditions(Physical)
(Environmental)
Low Dose RateIrradiation
Enhancement of Bio-Protective Functions
Resistance againstUntoward Conditions
Collaborators in CRIEPI
T. Iwasaki
Y. Hoshi T. Nomura
Y. Ina
H. Tanooka